Preeclampsia (also known as toxemia and referred to herein as PE) is a dangerous and volatile hypertensive disease that affects pregnant women, usually late in the second or third trimester, and postnatal women in the first six weeks after delivery. It is a leading cause of maternal, fetal and neonatal, morbidity and mortality. Further, both women and their children who survive PE are at greater risk for future adverse cardiovascular events.
The condition affects the kidneys, liver, brain, heart and placenta of the pregnant woman. PE occurs in approximately three to five percent of pregnancies and is only alleviated by ending the pregnancy, either by induction of labor or cesarean. PE most commonly occurs during a first pregnancy. The risk for preeclampsia is also known to be moderately increased for certain groups of pregnant women, including women who are over 35 years of age or under 18 years of age; women who are genetically predisposed to this condition; women who suffer from preexisting hypertension, diabetes, autoimmune diseases like lupus, various inherited thrombophilias like Factor V Leiden, or renal disease; obese women, and in women with multiple gestations (twins, triplets, and more). The single most significant risk for developing preeclampsia is having had preeclampsia in a previous pregnancy.
PE can develop either gradually or suddenly, and may remain mild throughout the pregnancy or become severe. PE is diagnosed by new onset protein in the urine (proteinuria) and high blood pressure. Common symptoms in addition to high blood pressure and proteinuria are elevated uric acid, vision problems such as blinking lights or blurry vision, persistent headaches, extreme swelling of hands and feet, fluid retention, pain in the upper right abdomen. If untreated, preeclampsia can damage the mother's liver or kidneys, cause pulmonary edema, deprive the fetus of oxygen, and cause eclampsia (seizures). A pregnant woman with signs of preeclampsia must be closely monitored by a physician. Moderate to severe preeclampsia is often treated in the hospital with bed rest, magnesium sulfate, and medication for high blood pressure. Unfortunately, delivery is still the only true “cure” for preeclampsia. In fact, when a woman has severe preeclampsia or is near term with mild to moderate preeclampsia, delivery is still the best remedy to date. Labor is then started with medication, unless a cesarean section is deemed necessary. Within the first few days following delivery, the mother's blood pressure usually returns to normal; however, with severe preeclampsia, it may take several weeks for blood pressure to return to normal.
The pathogenesis of PE has been investigated in the last decade, e.g., circulating factors emanating from the placenta have been identified in the blood that injure the endothelium, thereby producing maternal symptoms including hypertension and proteinuria. In contrast, PE etiology remains uncertain and infrequently addressed. One reason why so little is known about what causes PE is that the disease likely begins in early pregnancy, secondary in large measure to “shallow” placentation, i.e., deficient trophoblast (Tr) invasion of uterine spiral arteries, which starts in the 1st trimester. Normally, placental cells called Tr invade the endometrium, inner ⅓ of the myometrium and the uterine spiral arteries, ultimately remodeling the latter, which allows for large increases of blood flow, oxygen and nutrients to the developing placenta and fetus. In PE, Tr invasion is impaired and hence blood flow and oxygen delivery to the placenta and fetus is compromised, leading to release of factors from the placenta that circulate and injure the maternal endothelium, thereby producing disease manifestations. Thus, the Tr (“seed”) has been the focus of much investigative attention. In contrast, the uterine milieu (“soil”) has been less explored.
Endometrial maturation is a necessary precursor for healthy placentation. Stromal cells, uterine and glandular epithelial cells, as well as spiral arteries undergo distinct morphologic and functional changes, which begin before pregnancy in the late secretory/luteal (LS) phase of the menstrual cycle (“pre-decidualization”) continuing after conception (“decidualization”). Unfortunately, little data is available regarding whether certain elements in the LS endometrium (i.e., before conception) play a role in the later development of PE during pregnancy.
Because of the current lack of effective treatments for placental syndromes (i.e., PE and IUGR), there is a strong need to develop new therapeutic approaches for protecting both mother and child from the harmful effects of placental syndromes.